Method for preparing nitrogen-containing compounds

ABSTRACT

A synthesis method which comprises reacting NH group-containing compounds with thiocyanates, cyanamides, nitrites or esters in the presence of a silylating agent to synthesize the corresponding nitrogen-containing addition or substitution products. This method not only enables the direct and efficient synthesis of nitrogen-containing compounds including isothioureas, guanidines, amidines and amides, but it also has a wide range of applications and is suitable for large-scale synthesis.

RELATED APPLICATIONS

This is a divisional of co-pending application Ser. No. 10/296,925,nationalized Nov. 29, 2002, which application is the national phase ofinternational application PCT/JP01/04504, filed May 29, 2001.

TECHNICAL FIELD

The present invention relates to a novel method for preparingnitrogen-containing compounds (e.g., isothioureas, guanidines, amidines,amides) using amines.

BACKGROUND ART

Nitrogen-containing compounds including isothioureas, guanidines,amidines and amides are extremely important in the fields ofpharmaceutical or agricultural synthesis. Typical techniques used forpreparing these compounds from amines in a single step are shown below.

No technique is known to allow the direct synthesis of isothioureas fromamines and thiocyanates.

A technique for synthesizing guanidines from amines and cyanamides isknown from J. Med. Chem., 1996, 39, 4017, which reports reactionconditions involving heating the reaction mixture to 180° C. inconcentrated hydrochloric acid.

A technique for synthesizing amidines from amines and nitrites is knownfrom Chem. Pharm. Bull., 1997, 45, 987, which reports reactionconditions involving heating the reaction mixture to 150° C. in thepresence of aluminum chloride.

A technique for synthesizing amides from amines and esters is known fromTetrahedron Lett., 1996, 37, 2757, which reports the use oftrimethylaluminum for the synthesis. Also, another synthesis techniqueusing a silylating agent is known from Tetrahedron Lett., 1991, 32,3407, which reports the use of trimethylsilyl chloride for thesynthesis. However, in these techniques, the silylating agent is usedfor the protection of other functional groups and does not appear toenhance the synthesis reaction because the esters to be amidated arereactive enough to easily react with the amines in the absence of thesilylating agent. It is therefore impossible to predict from thesetechniques that the silylating agent enhances the amidation reaction ofless reactive esters. Still another technique using tinbishexamethylsilylamide is known from J. Org. Chem., 1992, 57, 6101.However, this technique is based on a concept distinct from that of thesynthesis reaction under consideration because the active species istin.

These conventional techniques require the use of highly reactive metalcompounds and/or extreme reaction conditions for the direct synthesis ofnitrogen-containing compounds (e.g., isothioureas, guanidines, amidines,amides) from amines. Such conventional techniques are therefore unableto have a wide range of applications and have been unsuitable forlarge-scale synthesis in terms of running costs, energy consumption andenvironmental impact. In view of the foregoing, there has been a demandto develop a preparation method that is available for a wider range ofapplications and that allows the efficient preparation ofnitrogen-containing compounds including isothioureas, guanidines,amidines and amides under mild reaction conditions.

DISCLOSURE OF THE INVENTION

As a result of our research efforts directed to overcoming the problemsstated above, we found that the use of a silylating agent for catalyzingthe reactions between NH group-containing compounds (e.g., amines) andthiocyanates, cyanamides, nitrites or esters enabled the direct andefficient synthesis of nitrogen-containing compounds of interest undermild reaction conditions. We also found that this synthesis techniqueusing a silylating agent had a wide range of applications and wassuitable for large-scale synthesis. The present invention has beenaccomplished on the basis of these findings.

In short, the present invention provides a method for preparingisothioureas, guanidines, amidines or amides, which comprises reacting aNH group-containing compound with a compound selected from the groupconsisting of thiocyanates, cyanamides, nitrites and esters (excludinghighly reactive esters) in the presence of a silylating agent.

Also, the present invention provides a method for preparing isothioureasand/or tautomers thereof, in which a NH group-containing compound ofgeneral formula (I-A):R^(1a)R^(2a)NH  (I-A)wherein

-   -   R^(1a) and R^(2a), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(1a)R^(2a)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        is reacted with a thiocyanate compound of general formula        (II-A):        R^(3a)SCN  (II-A)        wherein    -   R^(3a), which is the same or different, represents a hydrogen        atom or an optionally substituted monovalent hydrocarbon        residue,        in the presence of a silylating agent and, if necessary, in the        presence of an acid and/or a base to give an isothiourea        compound of general formula (III-A) and/or a tautomer thereof:        wherein    -   R^(1a), R^(2a) and R^(3a) are as defined above.

Further, the present invention provides a method for preparingguanidines and/or tautomers thereof, in which a NH group-containingcompound of general formula (I-B):R^(1b)R^(2b)NH  (I-B)wherein

-   -   R^(1a) and R^(2b), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(1b)R^(2b)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        is reacted with a cyanamide compound of general formula (II-B):        R^(3b)R^(4b)NCN  (II-B)        wherein    -   R^(3b) and R^(4b), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(3b)R^(4b)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        in the presence of a silylating agent and, if necessary, in the        presence of an acid and/or a base to give a guanidine compound        of general formula (III-B) and/or a tautomer thereof:        wherein    -   R^(1b), R^(2b), R^(3b) and R^(4b) are as defined above.

In addition, the present invention provides a method for preparingamidines and/or tautomers thereof, in which a NH group-containingcompound of general formula (I-C):R^(1c)R^(2c)NH  (I-C)wherein

-   -   R^(1c) and R^(2c), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(1c)R^(2c)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        is reacted with a nitrile compound of general formula (II-C):        R^(3c)CN  (II-C)        wherein    -   R^(3c) represents a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue,        in the presence of a silylating agent and, if necessary, in the        presence of an acid and/or a base to give an amidine compound of        general formula (III-C) and/or a tautomer thereof:        wherein    -   R^(1c), R^(2c) and R^(3c) are as defined above.

Furthermore, the present invention provides a method for preparingamides, in which a NH group-containing compound of general formula(I-D):R^(1d)R^(2d)NH  (I-D)wherein

-   -   R^(1d) and R^(2d), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(1d)R^(2d)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        is reacted with an ester compound (excluding highly reactive        esters) of general formula (II-D):        R^(3d)CO₂R^(4d)  (II-D)        wherein    -   R^(3d) represents a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, R^(4d) represents a hydrogen        atom, an optionally substituted monovalent hydrocarbon residue        or a substituted silyl group, or R^(3d)CO₂R^(4d) represents an        optionally substituted cyclic hydrocarbon,        in the presence of a silylating agent and, if necessary, in the        presence of an acid and/or a base to give an amide compound of        general formula (III-D):        wherein    -   R^(1d), R^(2d) and R^(3d) are as defined above.

BEST MODE FOR CARRYING OUT THE INVENTION

The method of the present invention can be applied where NHgroup-containing compounds are reacted with thiocyanates, cyanamides,nitriles or esters to synthesize nitrogen-containing addition orsubstitution products thereof.

As used herein, a NH group-containing compound literally refers to anycompound containing NH, including a linear or cyclic primary amine, alinear or cyclic secondary amine and a linear or cyclic imide.

As used herein, thiocyanates, cyanamides, nitrites and esters areintended to include, for example, compounds represented by generalformulae (II-A), (II-B), (II-C) and (II-D), respectively.

As used herein, isothioureas, guanidines, amidines and amides areintended to include, for example, compounds represented by generalformulae (III-A), (III-B), (III-C) and (III-D), respectively. Accordingto the present invention, these isothioureas, guanidines, amidines andamides are obtained through the addition or substitution reactions of NHgroup-containing compounds with thiocyanates, cyanamides, nitrites andesters, respectively. More specifically, isothioureas are derived fromthiocyanates, guanidines are derived from cyanamides, amidines arederived from nitrites, and amides are derived from esters.

According to the present invention, the nitrogen-containing compoundsincluding isothioureas, guanidines, amidines and amides can besynthesized as follows.

Preparation of Isothioureas

A compound of general formula (I-A):R^(1a)R^(2a)NH  (I-A)wherein

-   -   R^(1a) and R^(2a), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(1a)R^(2a)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        can be reacted with a compound of general formula (II-A):        R^(3a)SCN  (II-A)        wherein    -   R^(3a) represents a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue,        in an inert solvent or without using a solvent in the presence        of a silylating agent and, if necessary, in the presence of an        acid and/or a base to give an isothiourea compound of general        formula (III-A) and/or a tautomer thereof:        wherein    -   R^(1a), R^(2a) and R^(3a) are as defined above.

The tautomer as used herein refers to a compound of general formula(III-A′):

which may be generated when R^(2a) in general formula (III-A) is ahydrogen atom. Exactly the same can be said for the case where R^(1a) ingeneral formula (III-A) is a hydrogen atom.Preparation of Guanidines

A compound of general formula (I-B):R^(1b)R^(2b)NH  (I-B)wherein

-   -   R^(1b) and R^(2b), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(1b)R^(2b)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        can be reacted with a compound of general formula (II-B):        R^(3b)R^(4b)NCN  (II-B)        wherein    -   R^(3b) and R^(4b), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(3b)R^(4b)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        in an inert solvent or without using a solvent in the presence        of a silylating agent and, if necessary, in the presence of an        acid and/or a base to give a guanidine compound of general        formula (III-B) and/or a tautomer thereof:        wherein    -   R^(1b), R^(2b), R^(3b) and R^(4b) are as defined above.

The tautomer as used herein refers to a compound of general formula(III-B′) or (III-B″):

which may be generated when R^(2b) or R^(4b) in general formula (III-B)is a hydrogen atom. Exactly the same can be said for the case whereR^(1b) or R^(3b) in general formula (III-B) is a hydrogen atom.Preparation of Amidines

A compound of general formula (I-C):R^(1c)R^(2c)NH  (I-C)wherein

-   -   R^(1c) and R^(2c), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(1c)R^(2c)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        can be reacted with a compound of general formula (II-C):        R^(3c)CN  (II-C)        wherein    -   R^(3c) represents a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue,        in an inert solvent or without using a solvent in the presence        of a silylating agent and, if necessary, in the presence of an        acid and/or a base to give an amidine compound of general        formula (III-C) and/or a tautomer thereof:        wherein    -   R^(1c), R^(2c) and R^(3c) are as defined above.

The tautomer as used herein refers to a compound of general formula(III-C′):

which may be generated when R^(2c) in general formula (III-C) is ahydrogen atom. Exactly the same can be said for the case where R^(1c) ingeneral formula (III-C) is a hydrogen atom.Preparation of Amides

A compound of general formula (I-D):R^(3d)R^(2d)NH  (I-D)wherein

-   -   R^(1d) and R^(2d), which are the same or different, each        represent a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, or R^(1d)R^(2d)N represents an        optionally substituted monovalent cyclic hydrocarbon residue,        can be reacted with an ester compound (excluding highly reactive        esters) of general formula (II-D):        R^(3d)CO₂R^(4d)  (II-D)        wherein    -   R^(3d) represents a hydrogen atom or an optionally substituted        monovalent hydrocarbon residue, R^(4d) represents a hydrogen        atom, an optionally substituted monovalent hydrocarbon residue        or a substituted silyl group, or R^(3d)CO₂R^(4d) represents an        optionally substituted cyclic hydrocarbon,        in an inert solvent or without using a solvent in the presence        of a silylating agent and, if necessary, in the presence of an        acid and/or a base to give an amide compound of general formula        (III-D):        wherein    -   R^(1d), R^(2d) and R^(3d) are as defined above.

As used herein, highly reactive esters are intended to mean activecompounds capable of reacting with amines in the absence of a particularcatalyst to yield the corresponding amides. Examples include compoundsof general formula (II-D) wherein R^(d) is pentafluorophenyl orparanitrophenyl. Preparation methods using such ester compounds are notintended to be within the scope of the present invention. The conditionsunder which these four types of reactions occur will be described belowin more detail.

Examples of an inert solvent include hexane, cyclohexane, benzene,toluene, diethyl ether, diisopropyl ether, tert-butyl methyl ether,tetrahydrofuran, dioxane, dichloromethane, 1,2-dichloroethane andchloroform. Preferred for use are dichloromethane, 1,2-dichloroethane,benzene and toluene, or mixtures thereof.

The reaction may be performed at a temperature ranging from −78° C. tothe boiling point of the reaction mixture, preferably −20° C. to 110° C.

Examples of the silylating agent available for use include those whichare represented by the following formulae: R^(a)R^(b)R^(c)SiX,R^(a)R^(b)R^(c)SiOSO₂R^(d), R^(a)R^(b)R^(c)SiOSO₂R^(d), R^(a)R^(b)Si(OSO₂R^(d))₂, (R^(a)R^(b)R^(c)SiO)_(3-n)X_(n)PO,(R^(a)R^(b)R^(c)Si)R^(f)NCOR^(g), (R^(a)R^(b)R^(c)Si)NR^(i)R^(j) and(R^(a)R^(b)R^(c)SiO) (R^(a)R^(b)R^(c)SiN) CR^(k), wherein R^(a), R^(b)and R^(c), which are the same or different, each represent an optionallysubstituted linear, branched or cyclic C₁-C₁₀ alkyl group, an optionallysubstituted phenyl group or a halogen atom; X represents a halogen atom;Rd represents a hydrogen atom, an optionally substituted linear,branched or cyclic C₁-C₁₀ alkyl group, an optionally substituted phenylgroup, a halogen atom or R^(a)R^(b)R^(c)SiO; n is 0, 1 or 2; R^(f)represents R^(a)R^(b)R^(c)Si, a hydrogen atom, an optionally substitutedlinear, branched or cyclic C₁-C₁₀ alkyl group or an optionallysubstituted phenyl group; R^(g) represents a hydrogen atom, anoptionally substituted linear, branched or cyclic C₁-C₁₀ alkyl group, anoptionally substituted phenyl group, R^(a)R^(b)R^(c)SiO or(R^(a)R^(b)R^(c)Si)R^(f)N; R^(f)N; R^(i) and R^(j), which are the sameor different, each represent a hydrogen atom, an optionally substitutedlinear, branched or cyclic C₁-C₁₀ alkyl group, an optionally substitutedphenyl group or R^(a)R^(b)R^(c)Si, or NR^(i)R^(j) represents aring-forming substituent; and R^(k) represents a hydrogen atom, anoptionally substituted linear, branched or cyclic C₁-C₁₀ alkyl group, anoptionally substituted phenyl group or R^(a)R^(b)R^(c)SiO. Thesesilylating agents may be commercially available or may be prepared in aknown manner. Specific examples include Me₃SiCl (Me₃Si being hereinafterreferred to as TMS) , Et₃SiCl (Et₃Si being hereinafter referred to asTES), tBuMe₂SiCl (tBuMe₂Si being hereinafter referred to as TBS),Me₂PhSiCl, TMSO₂CCF₃, TESO₂CCF₃, TBSO₂CCF₃, TMSO₃SCl, (TMSO)₂SO₂,TMSO₃SCF₃, TESO₃SCF₃, TBSO₃SCF₃, (TMSO)₃PO, (TMSNH)₂CO, (TBSNH)₂CO,TMSNMeCHO, (TMS)₂NCHO, TMSNMeCOMe, (TMS)₂NCOMe, TMSNMeCOCF₃,TBSNMeCOCF₃, TMSNHCO₂TMS, (TMS)₂NH, (TMS)₃N, 1-TMSimidazole,1-TBSimidazole, (TMSO) (TMSN)CMe, (TBSO) (TBSN)CMe and (TMSO)(TMSN)CCF₃, with TMSCl, (TMSO)₂SO₂, TMSO₃SCF₃, TESO₃SCF₃, TBSO₃SCF₃ and(TMSO)(TMSN)CMe being preferred. These agents may be used alone or incombination in an amount of 0.1 to 10 equivalents, preferable 1 to 4equivalents, per amino group present in starting materials.

Further, the reaction may be performed in the presence of an acid and/ora base, if necessary. The acid may be any one of commonly-used Lewisacids and proton acids, or may be any one of inorganic acids (e.g., HCl,H₂SO₄, H₃PO₄) and organic acids (e.g., CF₃CO₂H, CF₃SO₃H, MeSO₃H). Thebase may be selected from inorganic bases (e.g., K₂CO₃, Na₂CO₃, KHCO₃,NaHCO₃), organic bases (e.g., pyridine, Et₃N, Et₂iPrN,N,N-dimethylaminopyridine) and organic metals (e.g., MeLi, nBuLi, sBuLi,tBuLi, MeMgCl, MeMgBr, EtMgCl, EtMgBr, iPrMgCl, iPrMgBr, tBuMgCl,tBuMgBr).

As used herein, the optionally substituted monovalent hydrocarbonresidue as R^(1a), R^(2a), R^(3a), R^(1b), R^(2b), R^(3b), R^(4b),R^(1c), R^(3c), R^(1d), R^(2d), R^(3d) and R^(4d) refers to a saturatedor unsaturated C₁-C₃₀ hydrocarbon residue which may be linear, branchedor cyclic and may further contain a heterocyclic ring. Examples include:

-   -   alkyl groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl,        n-hexyl, i-propyl, i-butyl, sec-butyl, tert-butyl, i-pentyl,        neopentyl, tert-pentyl, i-hexyl, cyclopropyl, cyclopropylmethyl,        cyclobutyl, 2-cyclobutylethyl, cyclopentyl, 1-cyclohexylnonyl,        cycloheptyl and cyclooctyl;    -   alkenyl groups such as vinyl, 1-propenyl, 1-butenyl, 1-pentenyl,        1-hexenyl, allyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 3-butenyl,        3-pentenyl, 3-hexenyl, 1-cyclopropenyl, 2-cyclopropenyl,        1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl,        2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl,        2-cyclohexenyl, 1-cyclopropenyl, 1-methylvinyl,        1-methyl-1-cyclopropenyl, 1-methyl-3-cyclopentenyl,        3-methyl-2-pentenyl, 3-methyl-2-cyclohexenyl, 1-ethyl-1-hexenyl        and 1-ethyl-2-cyclohexenyl;    -   alkynyl groups such as ethynyl, 1-propynyl, 1-butynyl,        1-pentynyl, 1-hexynyl, 2-propynyl, 2-butynyl, 2-pentynyl,        2-hexynyl, 3-butynyl, 3-pentynyl, 3-hexynyl,        1-methyl-2-propynyl, 3-methyl-1-butynyl, 1-ethyl-2-propynyl,        2-cyclooctynyl, 3-cyclodecynyl and 1-propyl-2-cyclotridecynyl;        and    -   aromatic groups such as phenyl, naphthyl, anthryl, phenanthryl        and pyrenyl.

The heterocyclic ring refers to a saturated or unsaturated cyclichydrocarbon containing one or more heteroatoms (e.g., nitrogen, oxygen,sulfur) as its ring members. Examples include aziridine, oxirane,thiirane, azetidine, oxetane, pyrrolidine, oxolane, thiolane, pyrrole,furan, thiophene, pyrazolidine, imidazoline, isoxazoline, oxazole,isothiazole, thiazole, pyridine, pyran, pyrimidine, pyrazine, indoline,benzofuran, benzothiophene, benzoxazole, chroman, isoquinoline,quinoxaline, carbazole and acridine.

As used herein, the cyclic hydrocarbon in the optionally substitutedmonovalent cyclic hydrocarbon residue as R^(1a)R^(2a)N, R^(1b)R^(2b)N,R^(3b)R^(4b)N, R^(1c)R^(2c)N and R^(1d)R^(2d)N refers to a saturated orunsaturated cyclic C₁-C₂₀ hydrocarbon which may contain, as its ringmembers, a heteroatom(s) in addition to the nitrogen atom. Examplesinclude aziridine, azetidine, pyrrolidine, pyrrole, pyrazolidine,imidazoline, oxazolidine, isoxazolidine, isothiazolidine, piperazine,morpholine, indole, dihydroisoquinoline and carbazole.

As used herein, the substituent of the substituted silyl group as R^(4d)refers to a linear, branched or cyclic C₁-C₁₀ alkyl group or a C₆-C₁₀aryl group. Examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, i-propyl, i-butyl, s-butyl, t-butyl, cyclohexyl and phenyl.

As used herein, the cyclic hydrocarbon as R^(3d)CO₂R^(4d) refers to asaturated or unsaturated cyclic C₂-C₂₀ hydrocarbon which may contain, asits ring members, a heteroatom(s) in addition to the oxygen atoms.Examples include tetrahydro-2-furanone, tetrahydro-2-pyrone, coumarin,isocoumarin, 2(3H)-benzofuranone and phthalide.

As used herein, examples of the substituent of the optionallysubstituted monovalent hydrocarbon residue as R^(1a), R^(2a), R^(3a),R^(1b), R^(2b), R^(3b), R^(4b), R^(1c), R^(2c), R^(3c), R^(1d), R^(2d),and R^(3d) include a halogen atom, −SiR^(e)R^(f)R^(g), —CONR^(i)R^(j),—CO²H, —NO₂, —N₃, —NR^(m)R^(n), —OR^(p), ═O, —S(O)_(n)R^(q), ═S and—P(O)(OR^(x)) (OR^(y)). R^(e), R^(f) and R^(g) in SiR^(e)R^(f)R^(g) eachrepresent a hydrogen atom, a halogen atom, a linear, branched or cyclicC₁-C₅ alkyl group or an optionally substituted C₆-C₁₅ phenyl group.Examples of a group represented by —SIR^(e)R^(f)R^(g) includetrimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dimethylphenylsilyland chlorodimethylsilyl.

R^(i) and R^(j) in CONR^(i)R^(j) each represent a hydrogen atom or asaturated or unsaturated monovalent C₁-C₂₀ hydrocarbon residue which mayhave a substituent(s) at any position and may be linear, branched orcyclic and may further contain a heteroatom(s) or a heterocyclic ring,or NR^(i)R^(j) represents a saturated or unsaturated cyclic C₂-C₂₀hydrocarbon which may have a substituent(s) at any position. Examples ofa group represented by NR^(i)R_(j) include amino, methylamino,benzylamino, ethylamino, dimethylamino, ethylmethylamino, pyrrolidinyl,piperidino, morpholino, acetamide, benzamide, N-methylacetamide,benzamide, t-butoxycarbonylamino, N-methyl-t-butoxycarbonylamino,methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino,isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino,phenylsulfonylamino, p-tolylsulfonylamino andp-chlorophenylsulfonylamino.

R^(m) and R^(n) in NR^(m)R^(n) each represent a hydrogen atom or asaturated or unsaturated monovalent C₁-C₂₀ hydrocarbon residue which mayhave a substituent(s) at any position and may be linear, branched orcyclic and may further contain a heteroatom(s) or a heterocyclic ring,or NR^(m)R^(n) represents a saturated or unsaturated cyclic C₂-C₂₀hydrocarbon which may have a substituent(s) at any position. Examples ofa group represented by NR^(m)R^(n) include amino, methylamino,benzylamino, ethylamino, dimethylamino, ethylmethylamino, pyrrolidinyl,piperidino, morpholino, acetamide, benzamide, N-methylacetamide,benzamide, t-butoxycarbonylamino, N-methyl-t-butoxycarbonylamino,methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino,isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino,phenylsulfonylamino, p-tolylsulfonylamino andp-chlorophenylsulfonylamino.

R^(p) represents a hydrogen atom or a saturated or unsaturatedmonovalent C₁-C₂₀ hydrocarbon residue which may have a substituent(s) atany position and may be linear, branched or cyclic and may furthercontain a heteroatom(s) or a heterocyclic ring. Examples of such ahydrocarbon residue include methyl, isopropyl, t-butyl, benzyl,p-methoxybenzyl, p-methoxyphenyl, cyclopropylmethyl, methoxymethyl,ethoxymethyl, benzyloxymethyl, methylthiomethyl, ethylthiomethyl,methoxycarbonyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl,triethylsilyl, t-butyldimethylsilyl and dimethylphenylsilyl.

In S(O)_(n)R^(q), n is 0, 1 or 2 and R^(q) represents a saturated orunsaturated monovalent C₁-C₂₀ hydrocarbon residue which may have asubstituent(s) at any position and may be linear, branched or cyclic andmay further contain a heteroatom(s) or a heterocyclic ring. Examples ofsuch a hydrocarbon residue include methyl, ethyl, isopropyl, phenyl,p-tolyl, p-chlorophenyl and benzyl.

R^(x) and R^(y) in P(O) (OR^(x)) (OR^(y)) each represent a hydrogen atomor a saturated or unsaturated monovalent C₁-C₂₀ hydrocarbon residuewhich may have a substituent(s) at any position and may be linear,branched or cyclic and may further contain a heteroatom(s) or aheterocyclic ring. Examples of such a hydrocarbon residue includemethyl, ethyl, isopropyl, t-butyl, phenyl, p-tolyl, p-chlorophenyl,p-methoxyphenyl, benzyl, p-methoxybenzyl, methoxymethyl,tetrahydropyranyl and t-butyldimethylsilyl.

EXAMPLES

The present invention will be further described in the followingexamples. The examples are provided for illustrative purposes only, andare not intended to limit the scope of the invention.

Example 1 Synthesis ofN-(5-(N-(S-ethylisothioureido))-2-(pyrrolidin-1-yl)benzyl)-2,2,2,-trifluoroacetamide

N-(5-Amino-2-(pyrrolidin-1-yl)benzyl)-2,2,2,-trifluoroacetamide (109.3mg) was dissolved in ethyl thiocyanate (328 μl) . To this solution,trimethylsilyl trifluoromethanesulfonate (83 μl) and thentrifluoromethanesulfonic acid (37 μl) were added dropwise at roomtemperature. After continued stirring for 3 hours at room temperature,saturated aqueous sodium bicarbonate was added to the solution, whichwas then extracted with chloroform. The extracted solution was driedover anhydrous sodium sulfate and evaporated under reduced pressure toremove the solvent. The resulting residue was purified by silica gelcolumn chromatography (liquid phase: chloroform/methanol=50/1) to givethe titled compound (134.1 mg, yield 94%).

¹H-NMR (200 MHz, CDCl₃) δ: 1.356 (3H, t, J=7.4 Hz), 1.8-2.1 (4H, m),2.8-3.2 (6H, m), 4.3-4.7 (4H, m), 6.7-6.9 (2H, m), 7.12 (1H, d, J=8.3Hz), 8.8-9.2 (1H, br).

Example 2 Synthesis of N-(p-tolyl)-S-ethylisothiourea

To a solution of toluidine (106.5 mg) in dichloromethane (5 ml),trimethylsilyl trifluoromethanesulfonate (198 μl) and then ethylthiocyanate (130.1 mg) were added dropwise at room temperature. Aftercontinued stirring overnight at room temperature, saturated aqueoussodium bicarbonate (1 ml) was added to the solution and further stirred.The dichloromethane layer separated from the above reaction mixture wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to give the titled compound (203.4 mg, yield 100%).

¹H-NMR (200 MHz, CDCl₃) δ: 1.358 (3H, t, J=7.3 Hz), 2.310 (3H, s), 3.026(2H, q, J=7.3 Hz), 3.7-4.3 (2H, br), 6.842 (2H, d, J=8.0 Hz), 7.118 (2H,d, J=8.0 Hz).

Example 3 Synthesis of N-p-totlylacetamide

To a solution of toluidine (12.8 mg) in dichloromethane (50 μl),trimethylsilyl trifluoromethanesulfonate (23.8 μl), ethyl acetate (23μl) and then pyridine (10.6 μl) were added dropwise at room temperature.After continued stirring overnight at room temperature, saturatedaqueous sodium bicarbonate (1 ml) was added to the solution and furtherstirred. The dichloromethane layer separated from the above reactionmixture was dried over anhydrous sodium sulfate and concentrated underreduced pressure to give the titled compound (18.7 mg, yield 100%).

¹H-NMR (200 MHz, DMSO-d₆) δ: 2.011 (3H, s), 2.232 (3H, s), 7.075 (2H, d,J=8.3 Hz), 7.449 (2H, d, J=8.3 Hz), 9.82 (1H, brs).

Example 4 Synthesis of N-p-tolylpropylamidine

To a solution of toluidine (12.3 mg) in propionitrile (100 μl),trimethylsilyl trifluoromethanesulfonate (23.8 μl) was added dropwise atroom temperature. After continued stirring for 1 day at roomtemperature, 2N aqueous sodium hydroxide was added to the solution,which was then extracted with ethyl acetate. The ethyl acetate layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure to give the titled compound (18.9 mg, yield 93%).

¹H-NMR (200 MHz, DMSO-d₆) δ: 1.098 (3H, t, J=7.57 Hz), 2.157 (2H, q,J=7.57 Hz), 2.232 (3H, s), 3.5-5.5 (1H, br), 6.674 (2H, d, J=8.3 Hz),7.046 (2H, d, J=8.3 Hz).

Example 5 Synthesis of N-p-tolylguanidine

To a solution of toluidine (14.2 mg) in dichloromethane (50 μl),trimethylsilyl trifluoromethanesulfonate (26.4 μl) and then cyanamide(16.7 μl) were added at room temperature. After continued stirringovernight at room temperature, concentrated aqueous sodium hydroxide wasadded to the solution, which was then extracted with ethyl acetate. Theethyl acetate layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give the titled compound (20.0mg, yield 100%).

¹H-NMR (200 MHz, DMSO-d₆) δ: 2.246 (3H, s), 5.0-5.9 (4H, br), 6.847 (2H,d, J=8.3 Hz), 7.085 (2H, d, J=8.3 Hz).

Mass (mass spectrometry) m/e: 149 (M+).

Example 6 Synthesis of N-benzyl-S-ethylisothiourea

Benzylamine (13.8 mg) was dissolved in ethyl thiocyanate (50 μl). Tothis solution, trimethylsilyl trifluoromethanesulfonate (25.7 μl) wasadded dropwise at room temperature. After continued stirring for 1 dayat room temperature, 2N aqueous sodium hydroxide was added to thesolution, which was then extracted with ethyl acetate. The ethyl acetatelayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure to give the titled compound (25.4 mg, yield 100%).

¹H-NMR (200 MHz, DMSO-d₆) δ: 1.198 (3H, t, J=7.3 Hz), 2.855 (2H, q,J=7.3 Hz), 4.286 (2H, s), 6.2-6.9 (2H, br), 7.1-7.4 (5H, m).

Example 7 Synthesis of p-tolylamidine Hydrochloride

To a solution of hexamethyl disilazane (484 mg) in dichloromethane (1ml), methanol (96 mg) was added dropwise at room temperature. Aftercooling on ice, trimethylsilyl trifluoromethanesulfonate (667 mg) wasadded dropwise to the solution. After the resulting suspension wasstirred for 1 hour at room temperature, p-tolunitrile (351 mg) was addeddropwise and further stirred for 2 nights at room temperature. Thesuspension was poured into 2N aqueous sodium hydroxide and extractedwith dichloromethane. The extracted solution was dried over anhydroussodium sulfate and evaporated under reduced pressure to remove thesolvent. The resulting residue was purified by column chromatography onsilica gel carrying amino groups (liquid phase:dichloromethane/methanol=5/1), followed by addition of 4N solution ofhydrogen chloride in ethyl acetate and evaporation under reducedpressure to remove the solvent, thereby giving the titled compound (7mg, yield 2%).

¹H-NMR (270 MHz, DMSO-d₆) δ: 2.41 (3H, s) , 7.43 (2H, d, J=8.0 Hz), 7.74(2H, d, J=8.0 Hz), 9.06 (2H, s), 9.30 (2H, s).

Example 8 Synthesis of N-allyl-p-tolylamidine

To a solution of allylamine (171 mg) in p-tolunitrile (117 mg),trimethylsilyl trifluoromethanesulfonate (222 mg) was added dropwise atroom temperature. After stirring for 2 nights at room temperature, 2Naqueous sodium hydroxide was added to the solution, which was thenextracted with dichloromethane. The extracted solution was dried overanhydrous sodium sulfate and evaporated under reduced pressure to removethe solvent. The resulting residue was purified by column chromatographyon silica gel carrying amino groups (liquid phase:dichloromethane/methanol=20/1) to give the titled compound (170 mg,yield 98%).

¹H-NMR (270 MHz, CDCl₃) δ: 2.38 (3H, s), 2.50-6.50 (2H, br), 4.00 (2H,s), 5.18 (1H, d, J=10.2 Hz), 5.29 (1H, d, J-17.2 Hz), 5.94-6.08 (1H, m),7.20 (2H, d, J-7.9 Hz), 7.48 (2H, d, J=7.9 Hz).

In the comparison example shown below, toluidine and ethyl thiocyanatewere reacted in the presence of a Lewis acid (titanium tetrachloride) toprepare N-(p-tolyl)-S-ethylisothiourea. The comparison example wascompared with Example 2 where a silylating agent was used for catalyzingthe reaction.

Comparison Example

To a solution of toluidine (215.0 mg) in dichloromethane (5 ml),titanium tetrachloride (61 μl) and then ethyl thiocyanate (350 mg) wereadded dropwise at room temperature. After heating at reflux for 3 hours,saturated aqueous sodium bicarbonate (1 ml) was added to the solutionand further stirred. The dichloromethane layer separated from the abovereaction mixture was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give the titled compound (177 mg,yield 45%).

Table 1 shows a comparison of yield between Comparison Example andExample 2. Table 1 indicates that the present invention enables thecompounds of interest to be prepared in extremely higher yields than thereactions using conventional catalysts such as Lewis acids. TABLE 1Yield Comparison Example  45% Example 2 100%Industrial Applicability

The present invention achieves the direct and efficient synthesis ofnitrogen-containing compounds including isothioureas, guanidines,amidines and amides, which are extremely important in the filed ofpharmaceutical or agricultural synthesis. This synthesis technique isavailable for a wide range of applications and suitable for large-scalesynthesis.

1. A method for preparing a guanidines, which comprises reacting a NHgroup-containing compound with a cyanamide in the presence of asilylating agent.
 2. The method according to claim 1, wherein a NHgroup-containing compound of formula (I-B):R^(1b)R^(2b)NH  (I-B) wherein R^(1b) and R^(2b), which are the same ordifferent, each represents a hydrogen atom or an optionally substitutedmonovalent hydrocarbon residue, or R^(1b)R^(2b)N represents anoptionally substituted monovalent cyclic hydrocarbon residue, is reactedwith a cyanamide compound of formula (II-B):R^(3b)R^(4b)NCN  (II-B) wherein R^(3b) and R^(4b), which are the same ordifferent, each represents a hydrogen atom or an optionally substitutedmonovalent hydrocarbon residue, or R^(3b)R^(4b)N represents anoptionally substituted monovalent cyclic hydrocarbon residue, in thepresence of a silylating agent and, if necessary, in the presence of anacid and/or a base to give a guanidine compound of formula (III-B)and/or a tautomer thereof:


3. The method according to claim 1, wherein the silylating agentcomprises one or more of compounds represented by the followingformulae: R^(a)R^(b)R^(c)SiX, R^(a)R^(b)R^(c)SiOCOR^(d),R^(a)R^(b)R^(c)SiOSO₂R^(d), R^(a)R^(b)Si (OSO₂R^(d))₂,(R^(a)R^(b)R^(c)SiO)_(3-n)X_(n)PO, (R^(a)R^(b)R^(c)Si)R^(f)NCOR⁹,(R^(a)R^(b)R^(c)Si)NR^(i)R^(j) and (R^(a)R^(b)R^(c)SiO)(R^(a)R^(b)R^(c)SiN)CR^(k), wherein R^(a), R^(b) and R^(c), which arethe same or different, each represents an optionally substituted linear,branched or cyclic C₁-C₁₀ alkyl group, an optionally substituted phenylgroup or a halogen atom; X represents a halogen atom; R^(d) represents ahydrogen atom, an optionally substituted linear, branched or cyclicC₁-C₁₀ alkyl group, an optionally substituted phenyl group, a halogenatom or R^(a)R^(b)R^(c)SiO; n is 0, 1 or 2; R^(f) representsR^(a)R^(b)R^(c)Si, a hydrogen atom, an optionally substituted linear,branched or cyclic C₁-C₁₀ alkyl group or an optionally substitutedphenyl group; R^(g) represents a hydrogen atom, an optionallysubstituted linear, branched or cyclic C₁-C₁₀ alkyl group, an optionallysubstituted phenyl group, R^(a)R^(b)R^(c)SiO or(R^(a)R^(b)R^(c)Si)R^(f)N; R^(i) and R^(j), which are the same ordifferent, each represent a hydrogen atom, an optionally substitutedlinear, branched or cyclic C₁-C₁₀ alkyl group, an optionally substitutedphenyl group or R^(a)R^(b)R^(c)Si, or NR^(i)R^(j) represents aring-forming substituent; and R^(k) represents a hydrogen atom, anoptionally substituted linear, branched or cyclic C₁-C₁₀ alkyl group, anoptionally substituted phenyl group or R^(a)R^(b)R^(c)SiO.
 4. The methodaccording to claim 3, wherein the silylating agent comprises a compoundrepresented by R^(a)R^(b)R^(c)SiOSO₂CF₂R^(d).
 5. The method according toclaim 4, wherein the compound represented byR^(a)R^(b)R^(c)SiOSO₂CF₂R^(d) is trimethylsilyltrifluoromethanesulfonate.
 6. The method according to claim 2, whereinthe silylating agent comprises one or more of compounds represented bythe following formulae: R^(a)R^(b)R^(c)SiX, R^(a)R^(b)R^(c)SiOCOR^(d),R^(a)R^(b)R^(c)SiOSO₂R^(d), R^(a)R^(b)Si (OSO₂R^(d))₂,(R^(a)R^(b)R^(c)SiO)_(3-n)X_(n)PO, (R^(a)R^(b)R^(c)Si)R^(f)NCOR^(g),(R^(a)R^(b)R^(c)Si)NR^(i)R^(j) and (R^(a)R^(b)R^(c)SiO)(R^(a)R^(b)R^(c)SiN)CR^(k), wherein R^(a), R^(b) and R^(c), which arethe same or different, each represents an optionally substituted linear,branched or cyclic C₁-C₁₀ alkyl group, an optionally substituted phenylgroup or a halogen atom; X represents a halogen atom; R^(d) represents ahydrogen atom, an optionally substituted linear, branched or cyclicC₁-C₁₀ alkyl group, an optionally substituted phenyl group, a halogenatom or R^(a)R^(b)R^(c)SiO; n is 0, 1 or 2; R^(f) representsR^(a)R^(b)R^(c)Si, a hydrogen atom, an optionally substituted linear,branched or cyclic C₁-C₁₀ alkyl group or an optionally substitutedphenyl group; R^(g) represents a hydrogen atom, an optionallysubstituted linear, branched or cyclic C₁-C₁₀ alkyl group, an optionallysubstituted phenyl group, R^(a)R^(b)R^(c)SiO or(R^(a)R^(b)R^(c)Si)R^(f)N; R^(i) and R^(j), which are the same ordifferent, each represent a hydrogen atom, an optionally substitutedlinear, branched or cyclic C₁-C₁₀ alkyl group, an optionally substitutedphenyl group or R^(a)R^(b)R^(c)Si, or NR^(i)R^(j) represents aring-forming substituent; and R^(k) represents a hydrogen atom, anoptionally substituted linear, branched or cyclic C₁-C₁₀ alkyl group, anoptionally substituted phenyl group or R^(a)R^(b)R^(c)SiO.
 7. The methodaccording to claim 6, wherein the silylating agent comprises a compoundrepresented by R^(a)R^(b)R^(c)SiOSO₂CF₂R^(d).
 8. The method according toclaim 7, wherein the compound represented byR^(a)R^(b)R^(c)SiOSO₂CF₂R^(d) is trimethylsilyltrifluoromethanesulfonate.